Introduction. Atrial fibrillation is associated with an increased
risk of ischemic stroke. The benefit of intravenous thrombolysis in
patients with acute ischemic stroke and atrial fibrillation is still
unclear. The aim of the study was to assess and compare the effects of
intravenous thrombolysis in stroke patients with and without atrial
fibrillation. Material and Methods. We analyzed stroke patients who were
treated with intravenous thrombolysis. Patients were divided into two
groups according to the presence of atrial fibrillation. Demographic,
clinical and radiological characteristics of patients were compared
between the two groups. The treatment efficacy was evaluated in relation
to the improvement of neurological status after 24 hours, and functional
recovery after three months. Binary logistic regression was used to
evaluate predictors of outcome. Results. From a total of 188 patients,
39.4% presented with atrial fibrillation. Patients with atrial
fibrillation were older (69.4 vs. 62.6 years; p <0.0001), with female
predominance (43.2% vs. 28.9%, p = 0.04) and had clinically more severe
stroke (National Institutes of Health Stroke Scale, score on admission
15.4 vs. 12.1; p = 0.0001). Significantly more patients without atrial
fibrillation (61.4% vs. 43.2%, p = 0.01) had a favorable clinical
outcome at three months after stroke. Nevertheless, atrial fibrillation
was not an independent predictor of poor outcome at three months after
stroke (p=0.66). Conclusion. Acute ischemic stroke patients, with atrial
fibrillation, treated with intravenous thrombolysis, had worse outcomes
than patients without atrial fibrillation did. However, it is mainly due
to older age and a more severe stroke in patients with atrial
fibrillation.

Atrial fibrillation (AF) is the most common heart rhythm disorder,
occurring in 2% of the general population, and in 20% of persons older
than 80 years [1]. Its incidence increases with age, and doubles in each
decade of life after the age of 55 years. Due to the extremely high
embolic potential, AF is the most important cardiac risk for the
development of cardio-embolic stroke [2-4]. The cardio-embolic stroke
clinically manifests as a severe neurological deficit, and
radiologically as a territorial (non-lacunar) infarction.

Until recently, intravenous thrombolysis (IVT) with recombinant
tissue plasminogen activator (rtPA) was the only approved therapy for
the treatment of patients with acute ischemic stroke (AIS) [5, 6],
improving the outcome if applied within 4.5 hours after the onset of
symptoms [7]. However, whether IVT is effective in AIS patients with AF
is still insufficiently clear. Large studies have proven the benefits of
IVT, but without testing the treatment efficacy in regard to the type
and etiology of stroke [7]. Some authors have shown that AF is a
predictor of a poor outcome in AIS patients treated with IVT [8],
although there are also opposite results [9]. Even today, the attitudes
on the efficacy and safety of IVT in AIS patients with AF are still
quite controversial.

The aim of our study was to evaluate the efficacy and safety of IVT
in AIS patients with AF compared to AIS patients without AF.

Material and Methods

This cross-sectional study analyzed the data of patients with AIS
who were treated with IVT at the Clinical Center of Vojvodina in Novi
Sad, Serbia. The data were prospectively collected in the period from
November 2008 to April 2015. On admission, all patients were examined by
a neurologist and their National Institute of Health Stroke Scale
(NIHSS) score was determined. This score is used for assessment of
severity of stroke and correlates with the size of cerebral infarction
[10]. All patients underwent brain computed tomography (CT) in or-der to
exclude intracranial hemorrhage (ICH). The Alberta Stroke Program Early
CT (ASPECT) score, that reflects the size of the cerebral ischemia [11],
presence of a hyperdense artery sign and leukoaraiosis, were assessed by
a radiologist. The following data were also recorded: age, gender, risk
factors (arterial hypertension, diabetes mellitus, hyperlipidemia, and
smoking), glucose level on admission, previous use of antiplatelet and
statin therapy, and the symptom onset-to-treatment time (OTT).

Twenty-four hours following the IVT treatment, the NIHSS score was
determined again and brain CT was repeated. Neurological improvement
showed a reduction in the NIHSS score of [greater than or equal to] 50%
compared with the NIHSS score on admission, or as NIHSS score [less than
or equal to] 3. Based on repeated CT findings, we determined the type of
cerebral infarction, and possible presence of hemorrhagic transformation
(HT). Development of symptomatic intracranial hemorrhage (sICH) in the
early stages of AIS (within seven days) was assessed according to the
European Cooperative Acute Stroke Study III (ECASS III) criteria [12].
The type of brain infarction was determined in accordance with the
Oxfordshire Community Stroke Project (OCSP) classification [13].
According to OCSP classification, there are four types of cerebral
infarction: total anterior circulation infarction (TACI), partial
anterior circulation infarction (PACI), posterior circulation infarction
(POCI) and lacunar infarction (LACI). All patients underwent
neurovascular status evaluation with ultrasound (carotid duplex
ultrasound, transcranial Doppler) and/or CT or magnetic resonance (MR)
angiography examinations. Functional outcome was assessed after three
months by the modified Rankin score (mRS) and favorable outcome was
defined as mRS 0-2 and unfavorable as mRS 3-6.

The presence of AF was defined as an evidence of these arrhythmias
on at least one electrocardiographic (ECG) recording, obtained either
from medical history or during hospitalization. After admission,
patients were monitored with ECG for at least 72 hours and, if
necessary, had additional recordings.

Patients were divided into two groups, according to the presence or
absence of AF, and they were compared with regard to demographic,
clinical and radiological characteristics, outcomes and adverse events.
The two-sample student t-test was used for comparisons of parametric
variables and chi-square ([chi] (2)) test or Fisher's exact test
for categorical variables. A p value of less than 0.05 (p < 0.05) was
regarded statistically significant. Binary logistic regression analysis
was used to evaluate predictors of neurological improvement, favorable
outcome and HT. The variables which were analyzed included age, gender,
baseline NIHSS score, OTT, glucose level on admission, presence of AF
and other risk factors (arterial hypertension, diabetes mellitus,
hyperlipidemia, smoking). Odds ratio (OR) was calculated with 95%
confidence interval (95% CI). Data were analyzed with the SPSS/PC Win
package version 20.0. The study was approved by the Ethical Board of the
Clinical Center of Vojvodina.

Results

The study included a total of 188 patients. Among them, 74 patients
(39.4%) had AF and 114 patients (60.6%) were without AF. Demographic,
clinical and radiological characteristics, as well as stroke subtypes of
the two groups are shown in Table 1. Patients with AF were older (69.4
vs. 62.6, p<0.0001) and there were more female patients (43.2% vs.
28.9%, p=0.04). In regard to risk factors, only smoking was
significantly more frequent among patients without AF (35.09% vs.
17.57%; p=0,009). Time from symptom onset to thrombolytic treatment
(OTT) did not differ significantly between the two groups of patients.
Regarding other clinically significant characteristics, only previous
use of antiplatelet therapy was significantly more frequent in patients
with AF (48.65% vs. 28.07%, p=0.004). On average, patients with AF had a
more severe stroke, i.e., a higher NIHSS score on admission (15.0 vs.
12.1, p<0.0001). The average baseline ASPECT score on brain CT did
not differ significantly between the two groups of patients. In patients
with AF, the most frequent were total and partial anterior circulation
infarctions (TACI 47.3%; PACI 45.9%), whereas lacunar infarctions were
significantly more frequent in patients without AF (LACI type 21.9% vs.
2.7%).

The outcome at 90 days post treatment is shown in Graph 1.
Approximately half of the patients without AF had a mRS score of 0 or 1
(mRS 0-23.1 %, mRS 1-25.4%), whereas majority of patients with AF had
mRS 6 (29.7%).

Comparison of outcomes and complications after application of IVT
is shown in Table 2. Neurological improvement at 24 hours was more
frequent in patients without AF (42.1% vs. 31.1%), although without a
statistical significance. A good outcome at three months (mRS 0 - 2) was
significantly more frequent in patients without AF (61.4% vs. 43.2%;
p=0.01). Furthermore, patients with AF commonly had a significant
hemorrhagic transformation (29.7% vs. 10.5%; p=0.0008), as well as
symptomatic intra-cerebral hemorrhage (9.5% vs. 0%; p=0.001). Lethal
outcome (mRS 6) within 90 days post treatment was also more frequent in
patients with AF (31.08% vs. 7.89%; p<0.0001).

The binary logistic regression analysis did not show AF to be an
independent predictor of poor (p=0.66) or lethal outcome (p=0.17) at
three months post IVT for AIS. In our study, predictors of an
unfavorable outcome (mRS 3 - 6) at three months were: older age
(p<0.0001; OR 1.08, 95% CI 1.03-1.13), a higher NIHSS score on
admission (p<0.0001; OR 1.31, 95% CI 1.19-1.45), a lower AS PECT
score on admission (p=0.013; OR 0.64, 95% CI 0.45-0.91) and higher
glucose levels on admission (p<0.0001; OR 1.28, 95% CI 1.13-1.45).
Predictors of lethal outcome (mRS 6) at three months were older age
(p<0.0001; OR 1.15, 95% CI 1.08-1.23), a higher NIHSS score on
admission (p<0.0001; OR 1.35, 95% CI 1.18-1.54) and presence of
diabetes (p=0.003; OR 5.95, 95% CI 1.86-18.97). In addition, AF was not
independently associated with neurological improvements at 24 hours
(p=0.38). Predictors of neurological improvement at 24 hours were a
lower NIHSS score on admission (p=0.003; OR 0.89, 95% CI 0.83-0.96), a
higher ASPECT score (p=0.027; OR 1.44, 95% CI 1.04-1.99) and absence of
diabetes (p=0.008; OR 0.27, 95% CI 0.1-0.7). However, AF was
independently associated with development of hemorrhagic transformation
(p<0.0001; OR 4.44, 95% CI 1.92 - 10.27).

Discussion

Our study showed that AIS patients with AF treated with IVT had a
worse outcome than patients without AF. Patients with AF were older (7
years, on average) and clinically had a more severe stroke (NIHSS score
higher by around 3 points) compared to patients without AF. Higher NIHSS
score in patients with AF was a result of larger cerebral infarction in
patients with AF. Lacunar infarction was found only in 2.7% of patients
(two patients) with AF, versus 21.9% of patients without AF. Development
of HT and sICH was significantly more frequent in patients with AF.
Similar results have been reported in some other studies [8, 14, 15]. In
a Japanese study of 85 patients, including 51.8% of patients with AF,
neurological improvement at seven days post IVT was considerably lower
in patients with AF (31.8% vs. 60%; p = 0.007) [8]. In addition, a
favorable outcome (mRS 0 - 2) at three months was also recorded in
significantly fewer patients with AF compared to those without AF (15.9%
vs. 46.3%, p = 0.002). Another study included 734 patients, of whom
21.1% had AF, a poor outcome (mRS 3-6) was reported in 52.3% of patients
with AF and in 35.2% of patients without AF (p < 0.001) [14]. The
mortality at 3 months following stroke was 21.9% in the group with AF
and 9% in the group without AF. Correspondingly, we found a higher
percentage of poor outcome and a higher mortality rate in the group of
patients with AF within three months following IVT. In a recent study
which examined predictors of early neurological improvement, AF was
independently associated with the absence of the major neurological
improvement 24 h after IVT [15]. In our study, early neurological im
provement was more common in patients without AF, but it was not
significant.

In the above-mentioned studies [8, 14], patients with AF were also
older and had a higher NIHSS score and more frequent HT, compared to
patients without AF, which is consistent with our findings. All of these
characteristics (older age, higher NIHSS score, common HT) are typical
of ischemic stroke caused by AF. As numerous studies have shown that age
and the NIHSS score on admission are the most important predictors of
outcome, independent of risk factors and the type of ischemic stroke, it
is expected that patients with AF would have a worse outcome because of
these characteristics [8, 14]. Thus, AF was not an independent predictor
of poor outcome, unlike older age and a higher NIHSS score. Similarly,
in our study, AF was also not an independent predictor of poor outcome,
as opposed to older age, higher NIHSS score and lower ASPECT score on
admission, as well as higher blood glucose levels on admission.
Moreover, some studies have shown that among patients with severe
clinical ischemic stroke (NIHSS score [greater than or equal to] 10) AF
was associated with a better outcome [9]. A study by Shang Feng et al.
analyzed the outcomes in subgroups of patients, depending on their NIHSS
scores (scores above and below 10). In the group of patients with a
NIHSS score over 10, a favorable outcome after three months was seen in
31% of patients with AF, and 8% of patients without AF (p= 0.005), and
mortality rates were 8% among cases with AF and 17% among patients
without AF (p = 0.168). This study concluded that, if NIHSS score on
admission was above 10, patients with AF had a better outcome after IVT
than those without AF. However, the most reliable results on the
efficacy of IVT in AIS patients with AF were obtained from studies that
included only patients with AF and compared those who were treated with
IVT and those not treated with IVT [16]. The conclusion of those studies
was that patients treated with IVT had a much better outcome compared to
those who were not treated with IVT. Similar results were obtained in a
multicenter study in China [17]. In this study, administration of IVT
was an independent predictor of a favorable outcome (OR 5.73, 95% CI 2.4
- 13.7; p < 0.001) in patients with AIS and AF.

From the pathophysiological point of view, the success of IVT
treatment in ischemic stroke caused by AF should be the most conclusive.
In most cases, cardio-embolic stroke is caused by the red thrombus,
which essentially consists of erythrocytes and fibrin [18, 19]. In cases
with red thrombus, IVT is much more effective, as demonstrated by animal
studies [20]. This finding is supported by clinical studies that have
demonstrated successful recanalization after the IVT therapy in ischemic
stroke caused by AF [21, 22]. The controversial results about the
efficacy of IVT in patients with AIS and AF can be explained by
additional factors that are often not considered when assessing the
outcome at three months after IVT. Namely, AF is associated mainly with
chronic heart failure [23, 24], which often causes reduced premorbid
functionality (premorbid mRS [greater than or equal to] 1) and a reduced
ability for maximum mobility during rehabilitation treatment. Given that
patients with AF are older and have a clinically more severe ischemic
stroke, they often, even after successful recanalization and initial
neurological improvement, have persisting neurological deficits
requiring extended hospitalization [24], which itself carries the risk
of further complications and after three months, patients do not reach
mRS [less than or equal to] 2, i.e., a favorable outcome.

Limitations of our study were the small number of patients with AF.
Secondly, the lack of a control group of AIS patients with AF who were
not treated with IVT, whose outcome would be compared with thrombolysis
patients. Also, the study included only patients with the same type of
cerebral infarction (TACI, PACI or POCI), and if it included patients
with different types, it would have given more reliable and perhaps
different results. However, this would require more patients, and it
should be a topic for future researches.

Conclusion

Patients with acute ischemic stroke and atrial fibrillation,
treated with intravenous thrombolysis, had a worse outcome compared with
patients without atrial fibrillation. However, patients with atrial
fibrillation were older, had more severe neurological deficits, larger
cerebral infarction and more commonly developed hemorrhagic
transformation, which were likely the main reasons for their poorer
treatment outcome.